Drug Removal by Therapeutic Plasma Exchange: a Wellness Check
Rami Ibrahim, MSc, PharmD
Assistant Professor, Department of Pharmacology and
Toxicology, College of Osteopathic Medicine, Michigan State University And
Clinical Assistant Professor, the School of Medicine, Wayne State University
Objectives • Upon completion of this presentation, the
participant will be able to:
1. Discuss drug-related pharmacokinetics characteristics which lead to more efficient removal by therapeutic plasma exchange (TPE)
2. Apply knowledge in clinical scenarios as to how to handle medications in patients actively receiving TPE
Conflict of interest statement
• No receipt of salary, royalties, honorarium, intellectual property rights/patent holder and consulting fees (e.g., advisory boards)
• No receipt of fees for non-CE services received directly from a commercial interest or their agents (e.g., speakers’ bureaus)
• No contracted research
• No ownership interest (stocks, stock options or other ownership interest excluding diversified mutual funds)
Outline • Introduction
• Drug removal by TPE principles
– Time between dose administration and TPE
– Relation between the amount removed and
biologic effect
– How to assess the amount removed?
• Future directions
Introduction • A 55-year-old female patient status post allogeneic
hematopoietic stem cell transplant for acute leukemia is on intravenous mycophenolate mofetil (MMF) 1g Q8H for the treatment of refractory gastrointestinal graft-versus-host-disease. She is initiated on TPE for the treatment of TTP:
• IV Cellcept dose given at 8:00 a.m. over 2 hours
• TPE initiated at ~ 8:30 a.m. for about 2 hours
Introduction • Pharmacokinetics:
– Trough (serum) total MMA* level prior to TPE = 1.8 mg/L
– MMA concentration in waste plasma = 1.4 mg/L
Ratio waste plasma/patient’s serum
concentration:
TPE eliminated a substantial amount of IV MMA when it
overlapped with the latter’s infusion for about 1.5
hours
* mycophenolic acid, the active ingredient of mycophenolate mofetil (MMF)
1.4/1.8 x 100= ~ 75%
Introduction: another case • Pediatric patient with pulmonary arterial
hypertension awaiting lung transplant
• On Treprostinil (Remodulin®) IV infusion
• TPE scheduled pre-transplant and post-transplant
Introduction
• TPE is used in a host of renal, hematological and neurological indications (to name a few)
• The likelihood of patients actively receiving TPE to be on multiple oral (or IV) medications is high
• TPE can remove these medications and, as such, can affect their disposition and, by extension, their therapeutic action
Introduction: Question #1
• Most of the literature evaluating drug removal by TPE is comprised of ?
1) Case reports of overdose situations
2) Case reports of therapeutic dose situations
3) Phase II pharmacokinetics studies of overdose exposure
4) Phase II pharmacokinetics studies of therapeutic dose exposure
Introduction: Question #1
• Most of the literature evaluating drug removal by TPE is comprised of ?
1) Case reports of overdose situations
2) Case reports of therapeutic dose situations
3) Phase II pharmacokinetics studies of overdose exposure
4) Phase II pharmacokinetics studies of therapeutic dose exposure
Introduction • Of all published reports, approximately 25% are
formal pharmacokinetic trials evaluating TPE’s impact on drug disposition
• The majority are case reports (predominately dealing with overdose exposure to medicines)
Ibrahim RB, et al. Pharmacotherapy 2007;27(11):1529-49
Drug removal by TPE: state of the literature
Ibrahim RB. Balogun RA. J Clin Apheresis 2013; 28: 73-77 Search term for the last 5 YEARS
Drug removal by TPE: state of the literature Year Drug Type of Publication (n) Comments
2013 Amphotericin case report (n=1) overdose
2013 Dabigatran ?; n=1
2013 Rituximab pharmacokinetic study (n=20)
2013 Valproic acid case report (n=1)
2013 Voriconazole case report (n=1)
2014 Ganciclovir case report (n=1)
2014 Warfarin prospective observational study (n=8)
pharmacodynamic study per se
2015 Interferon an open-label, single-center proof of concept study (n=6)
neutralizing antibodies assessed
2015 Bivalirudin case report (n=1) pediatric
2016 cisplatin case report (n=1) pediatric
2017 enoxaparin Case report (n=1) pediatric
2017 =
Plentiful evidence
High-level evidence (more studies than case reports)
Outline • Introduction
• Drug removal by TPE principles
– Time between dose administration and TPE
– Relation between the amount removed and
biologic effect
– How to assess the amount removed?
• Future directions
Drug Removal by TPE principles • In general, drugs are likely to be removed if:
Low volume of distribution (Vd)
and/or
high rate of plasma protein binding
Some have proposed that TPE ability to remove drugs occurs
when plasma protein binding of a substance is > 80% and
when the Vd is <0.2 L/kg
Ibrahim RB. Balogun RA. J Clin Apheresis 2013; 28: 73-77.
Ibrahim RB, Balogun RA. Semin Dial 2012 ;25(2):176-89.
Ibrahim RB, et al. Pharmacotherapy 2007;27(11):1529-49.
Drug Removal by TPE principles: Not just Vd and protein binding!
Ibrahim RB, Balogun RA. Semin Dial 2012 ;25(2):176-89.
Drug Removal by TPE principles: Time between dose administration and TPE
• Strong correlation between drug concentration before initiating TPE and the amount removed by the procedure
Ibrahim RB, et al. J Oncol Pharm Pract 2009;15(4):217-22
Drug Removal by TPE principles: Time between dose administration and TPE
• This correlation was also observed with:
– aspirin
– gentamycin
– rituximab
– thyroxine
– vancomycin
– valproic acid
• It is unclear if this parameter “trumps” the Vd and protein binding effects but a drug with a small Vd (~0.2L/kg) may be negligibly removed by TPE if given time to fully distribute
McClellan SD, et al. Ann Pharmacother 1997; 31:1132–1136. Kliegman RM, et al. J Pediatr 1980;
96:927–930. Bertino Jr JS, et al. Dev Pharmacol Ther 1982; 4:205–215. Binimelis J, et al. Intensive Care Med 1987; 13:33–38
White RL, et al. Clin Pharm 1984 ;3:396–402. Puisset F, et al. Br J Clin Pharmacol 2013;76(5):734-40
Drug Removal by TPE principles: Time between Dose administration and TPE
• Similar findings were reported with the antibiotic ceftazidime
Ibrahim RB, et al. J Oncol Pharm Pract 2009;15(4):217-22 Bozkurt F , et al. Eur J Clin Pharmacol 1987: 33(2):197-201
TPE started 1.5 hours from the end of a single-dose infusion
* Cefepime’s protein binding is 20% and Vd ~0.2 L/kg
Drug Removal by TPE principles: Time between dose administration and TPE
Immediate release formulation used
• Amphotericin overdose
Bastiaans DET, et al. Ther Drug Monit 2013;35:1-3
Wang GS, et al. Ann Pharmacother 2013;47:e9
Drug Removal by TPE principles: Time between dose administration and TPE
• Drugs with a low Vd (and low protein binding) are likely to be unaffected by TPE if given the time to distribute
• Scarce published pharmacokinetic analysis with drugs who have a low Vd (and high protein binding)
• While not giving drugs after TPE is customarily adopted, a drug like digoxin can be given immediately before TPE without any meaningful impact on its disposition
Keller F, et al. Arzneimittelforschung 1984;34:83-86
Keller F, et al. Clin Pharmacokinet 1985;10:514–523
Drug Removal by TPE principles: Time between dose administration and TPE
Digoxin was eliminated by not more than 1.5% even
immediately after dosing
Keller F, et al. Arzneimittelforschung 1984;34:83-86
Drug Removal by TPE principles: Question #2
• Which drug is likely to be removed the most by TPE? assume they’re all given 2 hours after TPE
1) Ceftriaxone (protein binding 96%; 0.1 L/Kg)
2) Cyclosporin (protein binding 90-98% and Vd 13 L/kg)
3) Digoxin (protein binding 25% and Vd 8 L/kg)
4) Vancomycin (protein binding 70% and Vd 0.4 L/kg)
Drug Removal by TPE principles: Answer to Question # 2
Ibrahim RB, Balogun RA. Semin Dial 2012;25(2):176-89 Fauvelle F, et al. Antimicrob Agents Chemother 1994;38:1519–1522
Bakken JS, et al. Antimicrob Agents Chemother 1993;37(5):1171–3.
Drug Removal by TPE principles: Time to distribution might be key
Not all Vds are equal
Apparent Vd – calculated at this time point
Steady State Vd – calculated at this time point, with
repeated doses
Adapted with permission from Katzung BG, ed. Basic & clinical pharmacology.
7th ed. New York: Lange Medical Books/McGraw-Hill; 1998:38,
Outline • Introduction
• Drug removal by TPE principles
– Time between dose administration and TPE
– Relation between the amount removed and
biologic effect
– How to assess the amount removed?
• Future directions
Drug Removal by TPE principles: Relation between the amount removed and biologic
effect
• In a significant number of compounds (e.g., B-blockers), blood levels do not correlate with clinical effects
• By extension, TPE may reduce blood levels of some drugs without altering their biologic effect
• e.g., monoclonal antibodies
Drug Removal by TPE principles: Relation between the amount removed and biologic
effect: Monoclonal Antibodies
Monoclonal antibody
Plasma protein binding; Vd
Time from TPE
Extracted by TPE; %
Basiliximab N/A; 4.8-8 L > 4 hours Yes; ~65%
Natalizumab N/A; ~6 L 10-14 days Yes; ~75%
Rituximab N/A; 2-5 L see discussion
Yes – see discussion
Okechukwu CN, et al. Am J Kidney Dis 2001;37:E11 Khatri BO, et al. Neurology 2009;72: 402-409
Drug Removal by TPE principles:
Relation between the amount removed and biologic effect:
Monoclonal Antibodies - Natalizumab
Khatri BO, et al. Neurology 2009;72: 402-409
Relation between the amount removed and biologic effect: Monoclonal Antibodies -
Natalizumab
• No pharmacokinetic analysis
Landi D, et al. Neurology 2007; 88(12):1144-1152
Drug Removal by TPE principles: Relation between the amount removed and biologic effect:
Monoclonal Antibodies - Rituximab Distribution half-life (t1/2α )~1.5-3 days and elimination t1/2 of ~ 20 days
Publications Time of rituximab dose from TPE
Results
Darabi K, et al. Am J Clin Pathol 2006;125:592–597
24-36 hours CD19+ and CD20+ B-cells depressed; activity against TTP maintained
McDonald V, et al. J Thromb Haemost 2010;8(6):1201-8
24 hours (?) Yes; ~70%
Scully M, et al. Blood 2011;118(7):1746-53
At a minimum 4 hours CD19+ B-cells depressed; ADAMTS13 activity increased and Anti-ADAMTS13 IgG decreased; appropriate hematologic response to TTP seen
Puisset F, et al. Br J Clin Pharmacol 2013;76(5):734-40
24-72 hours Yes; 47% - 54% (mostly with after the first session)
Drug Removal by TPE principles: Relation between the amount removed and
biologic effect: Monoclonal Antibodies - Rituximab
X dose 1 X dose 2 X dose 3 X dose 4
TPE
exposure = or slightly higher than
X dose 1 X dose 2
*Weekly intervals
** PK simulation
Puisset F, et al. Br J Clin Pharmacol 2013;76(5):734-40
Drug Removal by TPE principles:
Adapted with permission from Katzung BG, ed. Basic & clinical pharmacology.
7th ed. New York: Lange Medical Books/McGraw-Hill; 1998:38,
Monoclonal antibodies
Drug Removal by TPE principles: Relation between the amount removed and biologic
effect - Warfarin • Patients on warfarin (n=8; 121 TPEs)
• Pre-procedure INR influences the post-INR increase
• Similar effect on Factor II and fibrinogen
Zantek N, et al. J Clin Apher 2014; 29:75–82
5% albumin replacement
Drug Removal by TPE principles: Relation between the amount removed
and biologic effect – IFN-β
Giedraitiene N, et al. Med Sci Monit 2015;21:1512-9
Drug Removal by TPE principles: Check List
Time between dose administration and TPE
distribution half-life (t1/2α)
Plasma protein binding and Vd
Relationship between plasma levels (and removed drug) and biologic effect (or pharmacodynamic t1/2 is important)
Despite being removed, the biologic effect of some monoclonal antibodies was unaffected.
That said, the optimal time cut-off between dose and TPE initiation for each monoclonal antibodies is ill-defined
Drug Removal by TPE principles: Check List
Be wary: pharmacokinetics tenets (t1/2α, plasma protein binding and Vd ) can all change in:
Overdose Situations
e.g., ceftriaxone, levothyroxine
Outline • Introduction
• Drug removal by TPE principles
– Time between dose administration and TPE
– Relation between the amount removed and biologic effect
– How to assess the amount removed?
• Future directions
Drug Removal by TPE principles: Question # 3
• A patient presents with acute TTP and is slated for TPE. Which pharmacologic treatment can be given with TPE without its pharmacokinetics being affected by the procedure ?
1) Drug A (started 4 hours before; t1/2α= 0.5 hours)
2) Drug B (started 2 hours before; t1/2α= 0.5 hours)
3) Drug C (started 4 hours before; t1/2α= 24 hours)
4) Drug D (started 2 hours before; t1/2α= 24 hours)
Drug Removal by TPE principles: Question # 3
• A patient presents with acute TTP and is slated for TPE. Which pharmacologic treatment can be given with TPE without its pharmacokinetics being affected by the procedure ?
1) Drug A (started 4 hours before; t1/2α= 0.5 hours)
2) Drug B (started 2 hours before; t1/2α= 0.5 hours)
3) Drug C (started 4 hours before; t1/2α= 24 hours)
4) Drug D (started 2 hours before; t1/2α= 24 hours)
Drug Removal by TPE principles: Question # 4
• In your view, what is the most objective way to assess TPE influence on drug disposition?
1) calculate drug serum concentration before and after TPE
2) calculate TPE’s drug clearance
3) determine the amount of drug in waste plasma
4) determine TPE’s flow rate
Drug Removal by TPE principles: Question # 4
• In your view, what is the most objective way to assess TPE influence on drug disposition?
1) calculate drug serum concentration before and after TPE
2) calculate TPE’s drug clearance
3) determine the amount of drug in waste plasma
4) determine TPE’s flow rate
Drug Removal by TPE principles: how to assess the amount removed?
• The “Vancomycin” example
Publications type/# of patients
Endpoint Findings
Case report (n=1)1
Reduction in serum concentration
Yes; ~ 49% reduction
Case report (n=1)2
Reduction in serum concentration
Yes
Case report (n=1)3
Reduction in serum concentration
Yes; ~ 27% reduction
Case report (n=1)4 Reduction in serum concentration
No
PK trial (n=12)5 Total body stores (derived from amount in waste plasma)
No; 6.3% of total body stores
1Ann Pharmacother 2006;40:2279–2280. 2Ann Pharmacother 2001;35:1400–1402. 3Pharmacol Toxicol 1997; 81:245–246 . 4Ann Pharmacother 1996;30:1038. 5 Ann Pharmacother 1997; 31:1132–1136
PK=Pharmacokinetic
Drug Removal by TPE principles: how to assess the amount removed?
• The Vancomycin example: explanation
o The pitfalls of before/after TPE serum concentration evaluation:
– It does not take into account post-redistribution from tissues
Overestimation of removal
Dru
g S
eru
m
Co
nce
ntr
atio
n
Time
TPE
? Optimal cut-off
Drug Removal by TPE principles: how to assess the amount removed?
• Even if drug clearance is increased on TPE, it does not mean that significant amount of the drug is removed by TPE
• Clearance relies on serum concentrations, which decline faster than tissue levels
McClellan SD, et al. Ann Pharmacother 1997; 31:1132–1136
An example from the NCAA…sort of
% increase in PPG from 2014-2016:
PPG (2016)/PPG (2014) = 0.6/0.2 x 100 = 300%
Drug Removal by TPE principles: how to assess the amount removed?
• The Valproic acid example:
o The pitfalls of before/after TPE serum concentration evaluation:
– It does not take into account post-redistribution from tissues
Overestimation of removal
Dru
g S
eru
m
Co
nce
ntr
atio
n
Time TPE
? Optimal cut-off
32% cleared by TPE but only 8.6% of total dose removed
Bastiaans DET, et al. Ther Drug Monit 2013;35:1-3
Drug Removal by TPE principles: how to assess the amount removed?
o The pitfalls of before/after TPE serum concentration evaluation:
– The observed drop in serum concentration may not be due to TPE but normal endogenous elimination of the drug (e.g., cyclosporin removal*)
Overestimation of removal
Dru
g S
eru
m
Co
nce
ntr
atio
n
Time
TPE
* red cell exchange
The Cyclosporin example
Moorman MT, et al. J Clin Apher 2011;26:156–158.
Drug Removal by TPE principles: Other factors
• Concurrent renal failure
–Observation suggesting a trend to remove more drug when patients with TPE have underlying renal dysfunction
• Replacement fluid
– Equivocal (FFP and anticoagulants?)
Ibrahim RB, Balogun RA. Semin Dial 2012 ;25(2):176-89. Ibrahim RB, et al. Pharmacotherapy 2007;27(11):1529-49
Zantek N, et al. J Clin Apher 2014;29:75–82 Preston TJ, et al. World J Pediatr Congenit Heart Surg 2015;6(1):119-22
Introduction: another case
• Pediatric patients with pulmonary arterial hypertension awaiting lung transplant
• On Treprostinil (Remodulin®) IV infusion
• TPE scheduled pre-transplant and post-transplant
Future Directions • Scant data with the following therapeutic apheresis
procedures:
–erythrocytapheresis (exception cyclosporin*)
– leukapheresis
– immunoadsorption
–extracorporeal photopheresis
• Cyclosporin† (and tacrolimus ††) have been shown not to be affected by
TPE as their major distributive compartment is mainly erythrocytes, not plasma
††Am J Hosp Pharm 1994;51:1708. †J Heart Lung Transplant 2006; 25:483-485. ††Bone Marrow
Transplant 2000;25:449–451.†J Clin Apher 2011;26:156–158. † Transplantation 2003;75:1764–
765. †Prog Clin Biol Res 1990;337:363–365. † DICP 1991;25:211.
† Am J Kidney Dis 2001 ;37:1286–1289
Plentiful evidence
High-level evidence (more studies than case reports)
Sound methodology
Future directions
Conclusion • TPE has the ability to remove drugs
• The extent of the removal is a function of many factors, not the least of which are the drug’s own pharmacokinetics (at normal and overdose conditions)
• By removing the pharmacodynamic target, TPE can influence drug action – independent of the impact on the drug pharmacokinetics
Thank you